Analysis of anti-protective antigen IgG subclass distribution in recipients of anthrax vaccine adsorbed (AVA) and patients with cutaneous and inhalation anthrax

Semenova, Vera; Schmidt, Daniel S.; Taylor, Thomas H.; Li, H.; Steward‐Clark, Evelene; Soroka, Stephen; Ballard, Melissa M.; Quinn, Conrad P.

doi:10.1016/j.vaccine.2006.11.028

Cited by 8 publications

(5 citation statements)

References 29 publications

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“…The continued increase in antibody SHM, serum avidity, and neutralization titers in the first 6–12 months post-infection could have been driven either by persistent viral replication or by inert viral antigen trapped in follicular dendritic cell-associated immune complexes (Mandel et al, 1980). Persistent antigen may also explain why EBOV-specific IgG4 first appeared 1–2 years post-infection; prior studies have shown that repeated antigen exposures can lead to IgG4 class-switching (van de Veen et al, 2013, Semenova et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection

Davis

Jackson

McElroy

et al. 2019

Cell

161

196

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Summary Ebola virus (EBOV) remains a public health threat. We performed a longitudinal study of B cell responses to EBOV in four survivors of the 2014 West African outbreak. Infection induced lasting EBOV-specific IgG antibodies, but their subclass composition changed over time, with IgG1 persisting, IgG3 rapidly declining, and IgG4 appearing late. Striking changes occurred in the immunoglobulin repertoire, with massive recruitment of naïve B cells that subsequently underwent hypermutation. We characterized a large panel of EBOV glycoprotein-specific monoclonal antibodies (mAbs). Only a small subset of mAbs that bound glycoprotein by ELISA recognized cell-surface glycoprotein. However, this subset contained all neutralizing mAbs. Several mAbs protected against EBOV disease in animals, including one mAb that targeted an epitope under evolutionary selection during the 2014 outbreak. Convergent antibody evolution was seen across multiple donors, particularly among VH3–13 neutralizing antibodies specific for the GP1 core. Our study provides a benchmark for assessing vaccine-induced immunity.

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Section: Discussionmentioning

confidence: 99%

Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection

Davis

Jackson

McElroy

et al. 2019

Cell

161

196

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“…These toxins are classic A-B toxins, where lethal factor and edema factor represent the active moieties and protective antigen (PA) represents the cell-binding moiety (5,6,20). Humoral immunity to PA can successfully mediate protection from lethal challenges in animal models of inhalation anthrax, and the protection is correlated with the ability of PA-specific antibodies to neutralize LeTx in vitro in the toxin neutralization assay (TNA) (17,21,22,35,36,41).While PA-specific antibody titer has been shown to correlate with TNA titers in vitro, this relationship demonstrates variability among different studies and in different species (19,37,40,43,48,50). Most PA-specific neutralizing monoclonal antibodies (MAbs) show a more invariable linear relationship between concentration and toxin neutralization (4, 46).…”

mentioning

confidence: 99%

“…While PA-specific antibody titer has been shown to correlate with TNA titers in vitro, this relationship demonstrates variability among different studies and in different species (19,37,40,43,48,50). Most PA-specific neutralizing monoclonal antibodies (MAbs) show a more invariable linear relationship between concentration and toxin neutralization (4, 46).…”

mentioning

confidence: 99%

A Heterologous Helper T-Cell Epitope Enhances the Immunogenicity of a Multiple-Antigenic-Peptide Vaccine Targeting the Cryptic Loop-Neutralizing Determinant ofBacillus anthracisProtective Antigen

Oscherwitz

Cease

2009

Infect Immun

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We previously showed that a multiple antigenic peptide (MAP) displaying amino acids (aa) 305 to 319 from the 2␤2-2␤3 loop of protective antigen (PA) can elicit high-titered antibody that neutralizes lethal toxin (LeTx) in vitro and that this loop-neutralizing determinant (LND) specificity is absent in PA-immune rabbits. Some immune rabbits were, however, nonresponders to the MAP. We hypothesized that the immunogen elicited suboptimal major histocompatibility complex (MHC) class II-restricted T-cell help and that introduction of a functional helper T-cell epitope would increase MHC-restricted responsiveness and the magnitude and affinity of the antibody responses. In the current study, we characterized the T-and B-cell responses to LND peptides in mice, then designed second-generation MAP immunogens for eliciting LND-specific immunity, and tested them in rabbits. Bacillus anthracis is a gram-positive, spore-forming bacterium that naturally infects wildlife and livestock and, less frequently, humans. Since 2001, when spores of B. anthracis sent through the U.S mail resulted in infection in 22 individuals, including five fatal cases of inhalation anthrax, considerable effort has been directed toward reevaluating our preparedness for possible bioterrorist threats, including weaponized anthrax.The morbidity and mortality associated with inhalation anthrax are largely a result of the elaboration of two toxins, lethal toxin (LeTx) and edema toxin. These toxins are classic A-B toxins, where lethal factor and edema factor represent the active moieties and protective antigen (PA) represents the cell-binding moiety (5,6,20). Humoral immunity to PA can successfully mediate protection from lethal challenges in animal models of inhalation anthrax, and the protection is correlated with the ability of PA-specific antibodies to neutralize LeTx in vitro in the toxin neutralization assay (TNA) (17,21,22,35,36,41).While PA-specific antibody titer has been shown to correlate with TNA titers in vitro, this relationship demonstrates variability among different studies and in different species (19,37,40,43,48,50). Most PA-specific neutralizing monoclonal antibodies (MAbs) show a more invariable linear relationship between concentration and toxin neutralization (4, 46). These findings can be reconciled, in part, by the fact that only a fraction of the polyclonal antibody produced in response to vaccination with PA contributes to LeTx neutralization (4,39,40). Indeed, analyses of human and murine MAbs suggest that whereas immunization with whole PA elicits antibodies to a wide range of sequences within the protein, the repertoire of neutralizing antibodies is considerably more focused, limited perhaps to only a couple of major regions in PA, including the anthrax toxin receptor binding region in domain 4 and the lethal factor-and edema factor-binding regions in domain 1 (4,24,25,40). Though PA-specific antibody may contribute to protection through mechanisms other than neutralization, for example, by facilitating opsonization of spores (...

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“…Moreover, serum antibodies from recovered cutaneous anthrax patients provide a record of exposure of the immune system to antigens that are not present in anthrax vaccines given in the western world [28,38,39]. While there have been many case reports detailing clinical information on individual patients, fewer studies have examined the cellular [17,18,[40][41][42] or humoral [16,18,19,[43][44][45][46][47][48][49] immune response to cutaneous anthrax infection. The present study is the first to investigate three facets of cutaneous infection: the impact of disease severity on the humoral immune response, the fine specificity of the anti-toxin antibody response, and incidence of the humoral response to BclA and anthrose.…”

Section: Discussionmentioning

confidence: 99%

Toxin-neutralizing antibodies elicited by naturally acquired cutaneous anthrax are elevated following severe disease and appear to target conformational epitopes

et al. 2020

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Understanding immune responses to native antigens in response to natural infections can lead to improved approaches to vaccination. This study sought to characterize the humoral immune response to anthrax toxin components, capsule and spore antigens in individuals (n = 46) from the Kayseri and Malatya regions of Turkey who had recovered from mild or severe forms of cutaneous anthrax infection, compared to regional healthy controls (n = 20). IgG antibodies to each toxin component, the poly-γ-D-glutamic acid capsule, the Bacillus collagen-like protein of anthracis (BclA) spore antigen, and the spore carbohydrate anthrose, were detected in the cases, with anthrax toxin neutralization and responses to Protective Antigen (PA) and Lethal Factor (LF) being higher following severe forms of the disease. Significant correlative relationships among responses to PA, LF, Edema Factor (EF) and capsule were observed among the cases. Though some regional control sera exhibited binding to a subset of the tested antigens, these samples did not neutralize anthrax toxins and lacked correlative relationships among antigen binding specificities observed in the cases. Comparison of serum binding to overlapping decapeptides covering the entire length of PA, LF and EF proteins in 26 cases compared to 8 regional controls revealed that anthrax toxin-neutralizing antibody responses elicited following natural cutaneous anthrax infection are directed to conformational epitopes. These studies support the concept of vaccination approaches that preserve conformational epitopes.

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Analysis of anti-protective antigen IgG subclass distribution in recipients of anthrax vaccine adsorbed (AVA) and patients with cutaneous and inhalation anthrax

Cited by 8 publications

References 29 publications

Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection

Longitudinal Analysis of the Human B Cell Response to Ebola Virus Infection

A Heterologous Helper T-Cell Epitope Enhances the Immunogenicity of a Multiple-Antigenic-Peptide Vaccine Targeting the Cryptic Loop-Neutralizing Determinant ofBacillus anthracisProtective Antigen

Toxin-neutralizing antibodies elicited by naturally acquired cutaneous anthrax are elevated following severe disease and appear to target conformational epitopes

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